title: Synthesis and biological evaluation of [11C]MK-912 as an alpha2-adrenergic receptor radioligand for PET studies.
abstract: In vitro studies showed that MK-912 ((2S, 12bS)1',3'-dimethylspiro(1,3,4,5',6,6',7,12b-octahydro -2H-benzo[b]furo[2,3-a]quinolizine)-2,4'-pyrimidin-2'-one) is a potent alpha2-adrenergic receptor antagonist with high affinity (Ki = 0.42, 0.26 and 0.03 nM to alpha2A, alpha2B and alpha2C, respectively) and high selectivity (alpha2A/alpha1A = 240; alpha2A/D-1 = 3600; alpha2A/D-2 = 3500; alpha2A/5-HT1 = 700; alpha2A/5-HT2 = 4100). The compound was labeled with 11C and evaluated in rodents and monkey as a specific radioligand for studying alpha2-adrenergic receptors using PET. [11C]MK-912 was synthesized by methylation of its desmethyl precursor, L-668,929, with [11C]CH3I in (Bu3O)P=O at 85 degrees C for 8 min followed by purification with HPLC in 18% yield in a synthesis time of 45 min from end of bombardment (EOB). The specific activity was 0.83-0.93 Ci/micromol and the radiochemical purity was 97%. The initial uptake of [11C]MK-912 in mouse brain, heart, lung, liver and kidney was high (5%, 4%, 5%, 17% and 8% per gram of organ, respectively, at 5 min postinjection) and the activities were then slowly cleared from these organs. The uptake of [11C]MK-912 in rat olfactory tubercle, a brain region with high density of alpha2-adrenergic receptors, was reduced by 30%, and the ratio of radioactivity in olfactory tubercle/cerebellum was reduced from 2:1 to 1:1 by coinjection of [11C]MK-912 with a potent alpha2-adrenergic receptor antagonist, atipamezole (3 mg/kg), indicating that compound 2 binds to alpha2-adrenergic receptors. However, a PET study in a rhesus monkey revealed that the initial influx of [11C]MK-912 into various brain regions (cerebellum, cortex, olfactory tubercle and striatum) was high (0.02%/cc), and the radioactivity was then washed out slowly and without significantly differential retention in these brain regions. This, coupled with the fact that none of the high-density alpha2-adrenergic receptor brain regions exceeds a few millimeters in diameter, suggests that [11C]MK-912 is probably not an ideal radioligand for studying alpha2-adrenergic receptors in humans using commercially available PET.
authors.affiliation: Center for Metabolic Imaging, Creighton University, Omaha, NE, USA.
authors.forename: C
authors.initials: C
authors.lastname: Shiue
authors.forename: R C
authors.initials: RC
authors.lastname: Pleus
authors.forename: G G
authors.initials: GG
authors.lastname: Shiue
authors.forename: J A
authors.initials: JA
authors.lastname: Rysavy
authors.forename: J J
authors.initials: JJ
authors.lastname: Sunderland
authors.forename: K G
authors.initials: KG
authors.lastname: Cornish
authors.forename: S D
authors.initials: SD
authors.lastname: Young
authors.forename: D B
authors.initials: DB
authors.lastname: Bylund
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D008024:Ligands; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D011807:Quinolizines / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: D000317:Adrenergic alpha-Antagonists; D002250:Carbon Radioisotopes; D008024:Ligands; D011807:Quinolizines; D019275:Radiopharmaceuticals; D018341:Receptors, Adrenergic, alpha-2; C054290:L 657743